JPS63174957A - Production of 4-amino-3-hydroxylactic acid - Google Patents

Abstract

PURPOSE:To readily and economically obtain a compound useful as a medicine having action such as improvement of cerebral metabolism, increase of cerebral blood stream, vasodepression, sedation, etc., in high purity and yield, by hydrogenating 4-azide-3-hydroxylactic acid. CONSTITUTION:4-Azide-3-hydroxylactic acid expressed by the formula derived from an optically active epichlorohydrin is reacted in the presence of metallic catalyst (e.g. palladium, platinum) in a solvent such as methanol, etc., under room temperature of 20-25 deg.C at ordinary pressure for 3-15hr to provide the aimed product. Palladium-carbon powder having about 10% palladium content is especially excellent from view point of yield and economics as the catalyst and is used in an amount of 0.5-50wt.% based on the raw material expressed by the formula.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a method for producing 4-amino-3-hydroxyacetic acid.

4-Amino-3-hydroxyacetic acid has medicinal effects such as improving brain metabolism, increasing cerebral blood flow, lowering blood pressure, and sedating, and among its optical isomers, the (R) form exhibits biological activity. It is. Currently, 4-amino-3-hydroxybutyric acid is used in racemic form, and therefore it is important to obtain only the (R) form in high purity. Also (R)-
(R) derived from 4-amino-3-hydroxybutyric acid
-Runitin is also called vitamin BT and is attracting attention as a nutritional supplement and medicine due to its excellent biological activity.

(Prior Art) Conventionally, the following method is known as a method for synthesizing (R)-4-amino-3-hydroxybutyric acid.

(1) Using ascorbic acid as a starting material, (R)
Method via -4-amino-3-hydroxybutyronitrile (J, Am, Chem, Soc, 1st
Volume 02.

6304 pages (1980)).

(2) Using shi-arabinose as a starting material, (R)-4
-method via amino-3-hydroxymethyl acetate (
Acta, Chem, 5cand, B, Volume 37, Page 344.

(1983)).

(3) Asymmetrically synthesized by Sharpless oxidation, (R)-
Method via 3,4-epoxybutyric acid (J, Org.

Chem, vol. 49, p. 3707, (1984
)).

(4) A method of introducing an asymmetric carbon by asymmetric hydrolysis of a β-keto ester using enzymes or microorganisms (Chinese etrahedron Lett, 2nd
Volume 5.

5235 pages (1984), Tetrahedron L
ett, , vol. 26.

101 pages (1985)).

(5) A method using (23,4R) -N-acetyl-4-hydroxyproline as a starting material (5ynthes
is.

424 pages, (1986)).

(Problems to be Solved by the Invention) All of the above methods require 4-azide-3 as the raw material of the present invention.
-Hydroxybutyric acid, and among the above methods, (1) and (2) have the disadvantage of having a very large number of steps, and (3) has the disadvantage that the obtained (R)-4-amino-3 -Hydroxyacetic acid has low optical purity, (4) has a low reaction concentration or the optical purity of the product is low, and (5) requires expensive starting materials.

(Means for Solving the Problems) The present inventors have proposed an optically active (R)-4-amino-3 which does not have the above-mentioned problems, has simple reaction operations, and has high optical purity.
- As a method for producing hydroxybutyric acid in high yield, the optical activity (R
) - A method using epichlorohydrin as a starting material was investigated. As a result, it was found that the object of the present invention with extremely high optical purity can be obtained by a method using a novel optically active butyric acid derivative obtained by synthesizing an optically active azide derivative from epichlorohydrin and roughly oxidizing this as a raw material. This is what I found.

The present invention is characterized in that 4-azido-3-hydroxybutyric acid represented by the following formula is hydrogenated in the presence of a catalyst.
This is a method for producing hydroxybutyric acid.

The method of the present invention can improve the optical purity of the target product by using optically active 4-azido-3-hydroxybutyric acid (E) with high optical purity obtained through the following reaction steps using optically active epichlorohydrin as a raw material. Those with significantly high values can be obtained in high yields.

A B C Azide derivative l-I H D E Azide derivative Butyric acid derivative F
G Acetic Acid Derivatives In the above reaction step, the optically active azide derivatives C and D and the optically active butyric acid derivatives E and F, which are the raw materials of the present invention, are new compounds that have not been previously described in any literature, and have been filed separately by the applicant.

The above F compound (optically active 4-
Azido-3-hydroxybutyric acid) is produced using optically active epichlorohydrin as a raw material, and the method that goes through the above reaction steps is advantageous because the intermediate can be easily isolated and a product with high optical purity can be obtained in high yield. be.

The raw material compound (optically active 4-azide-
The method for producing (S3-hydroxybutyric acid) will be explained below using an example using optically active (R)-epichlorohydrin with high optical purity obtained by the invention of the earlier application as a raw material.
) The same is true when using epichlorohydrin,
In this case, (S)-4-azido-3-hydroxybutyric acid is obtained, which in turn is the final compound (S)-4-
Converted to amino-3 hydroxybutyric acid.

:B) Reaction for obtaining B from A This reaction is carried out by adding an organic compound corresponding to R1 of B to (R)-epichlorohydrin (A) in the presence of a cupric compound such as cupric cyanide or cupric iodide. This is done by acting on an alkali metal compound RIM.

1?1) H in 1 is preferably lithium or sodium, and an organic group of R1, such as an alkali metal compound bonded directly to the carbon of the aromatic ring or to the carbon of a double bond, is used. R1 is an aromatic hydrocarbon residue such as a phenyl group,
It is an olefin residue such as a vinyl group or a hydrophobic substituent that can be easily converted into a carboxylic acid such as a cyclopentadienyl group, and usually an organic group as shown in R1)1 below is used.

That is, specific examples of RIH include phenyllithium, 2-methylphenyllithium, 2,3-dimethylphenyllithium,
Examples include phenyllithium having 1 to 5 methyl groups and methoxyl groups such as 2-methoxyphenyllithium, 1-naphthyllithium, 2-naphthyllithium, etc. As olefin alkali metal derivatives, CH2=ct+ci,
CH3-CH=C(CH3)Li, n-C7H
15CH=Ct(Li is included, and examples thereof include cyclopentadiene or substituted cyclopentadiene alkali metal derivatives. Among these RlH, phenyllithium is most preferable in terms of ease of acquisition and yield.

In this reaction, the amount of the monovalent copper compound used is preferably 1 to 1.1 equivalents, and the optimal amount of R'H is 2 to 2.2 equivalents relative to the raw material epichlorohydrin. The reaction is usually carried out using anhydrous ethers such as ethyl ether, tetradidrofuran, etc. as a solvent at a reaction temperature of -90 to -45°C for 2 to 3 hours.

(b) Reaction for obtaining C from B This reaction is carried out by reacting compound B with an alkali metal azide salt, such as sodium azide or potassium azide. The solvents used are dimethylformamide, dioxane, and acetonitrile-water (mixed system).
This is achieved at 60-100°C for 5-20 hours. This is carried out using 2 to 10 equivalents of sodium azide or potassium azide as the alkali metal azide salt relative to compound B. In particular, the optimal reaction conditions are to use 2 equivalents of sodium azide, dimethylformamide as the solvent, and 80° C. for 14 hours.

(c) Reaction for obtaining D from C This reaction is a reaction in which the above-mentioned optically active (R)-azide derivative (C) is usually acylated by reacting an acid anhydride or an acid halide with a base. R in [)M is an acyl group (-C0R2).

However, in addition to R2 (lower alkyl group or phenyl group),
A t-7 toxycarbonyl group is chosen. In the case of acyl groups, acylating agents include acid anhydrides such as acetic anhydride, propionic anhydride, benzoic anhydride, or acid halides such as acedel chloride, acetyl bromide, propionyl chloride, propionyl bromide, Benzoyl chloride, benzoyl bromide, etc. are used. For introducing a t-butoxycarbonyl group, it is preferable to use t-butoxycarboxylic acid anhydride. Pyridine, triethylamine, etc. are used as the base.

The amount of the acid anhydrides or acid halides used is preferably in the range of 1 to 6 equivalents relative to the azide derivative (C), and the amount of the bases to be used is preferably in the range of 2 to 20 equivalents. The reaction is accomplished by carrying out the reaction at sub-temperature (20-25°C) for 24-100 hours. When using pyridine or triethylamine as a base, methylene chloride, chloroform, or carbon tetrachloride is preferably used as the solvent.

(d) Reaction to obtain E from D This reaction is an optically active (R)-azido derivative (D compound)
It is an oxidation reaction that is usually carried out in the coexistence of an alkali metal periodate and ruthenium chloride.

These reactants are preferably 2 to 18 equivalents of alkali metal periodate and 0.022 equivalents of ruthenium chloride relative to compound D. The reaction conditions were Sharpless conditions (J, Or
g, Chem, 46%, page 393B, (1
981)), and is usually achieved by using carbon tetrachloride diacetonitrile:water = 2:2:3 (volume) as a solvent and carrying out the reaction at subtemperature (25'C) for 0.5 to 120 hours.

(e) Reaction to obtain F from E This reaction produces the F compound ((R)
-4-azido-3-hydroxyacetic acid). When R in compound E is a t-butoxycarbonyl group, acids 2 such as hydrochloric acid and formic acid are used.

This is done by applying acetic acid, trifluoroacetic acid, etc. When R in the above E is an acyl group, the reaction can be carried out by reacting with a base such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, etc. When using acids, trifluoroacetic acid is preferably used in terms of ease of distillation under reduced pressure after the reaction and yield.

As described above, the optically active (
1? )-4-azido-3-hydroxybutyric acid is synthesized. In the above explanation, we mainly talked about the optically active compound, but the racemic compound mentioned above can also be obtained in the same way using racemic epichlorohydrin, and thus the racemic target compound 4- Aminol 3-hydroxybutyric acid can be obtained.

The object of the present invention is achieved by hydrogenating the terminal azide of the above-mentioned raw material compound in the presence of a catalyst.

Any catalyst used in this type of reaction can be used, but metal catalysts such as palladium, platinum, etc. are particularly suitable, with palladium being preferred from the viewpoint of yield and economy. In particular, palladium-carbon powder with a palladium content of about 10% is excellent. The appropriate amount of the catalyst to be used is in the range of 0.5 to 50% by weight based on the raw material compound. The reaction is usually carried out at the lowest temperature (20 to 25°C) and normal pressure for 3 to 15 hours.

Solvents used in the reaction include alcohols,
Examples include methanol, ethanol, lowobanol, isopropanol, t-butanol, or mixtures thereof with water, and ethers such as ethyl ether, tetrahydrofuran, dioxane, etc., but methanol is usually preferably used.

(Example) Synthesis Example 1 (Compound B, (R)-1-chloro-2-hydroxy-3
- Synthesis of phenylpropane) 5.32 g of cupric cyanide (
59.40 mmol) of dry tetrahydrofuran solution was added, and the phenyllithium solution 45.7. W! (2.60 mol solution of cyclohexane:ether = 70:30 (volume), 0.1189 mol of phenyllithium) was added dropwise and stirred at the same temperature for 30 minutes. Then, at -45°C, the optical purity was 99%.
Above (R)-epichlorohydrin 4.2. W (54
, 05 mmol) was added dropwise and stirred at the same temperature for 1.5 hours. After the reaction, the reaction solution was extracted with ether containing a saturated ammonium chloride aqueous solution. Saturate this ether layer with sodium bicarbonate water.

After washing successively with saturated brine and drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 10.40 (l) of a pale yellow oil. This was subjected to column chromatography packed with 300 l of silica gel, and ether :Hexane=1=9(
Capacity> Colorless oily (R)-1-chloro-2-hydroxy-3-phenylpropane (B) a, 39
(1 (yield 93%)) was obtained.

The properties of the above compound B are as follows.

Boiling point: 94°C (18mm Hg, Kugelrohr (K)
LIgelrOhr > Depends on the device) [α]o −3
,72° (C=1.02.CHCl3)I Rv
max cm-13400 (OR) NMR (CDC1:
+ ) δ: 2.22 (IH, d, J = 5.2H2゜ex
changeable with 020, 044
>2.90 (2H, d, J= 6.6Hz, ar
omatic-CH2-) 3.47-3.62 (2M, m, -CH2-C
1) 3.90-4.20 (IH, m, -CH(OH
) -)7.29 (5H,m, aromatic
H) MS (m/e), 170 (M10),
91 (100%) Elemental analysis C9H110C1 theoretical value C: 63.35. H:6.
50°CJ! : 20.78 Measured value C: 63.04. H: 6.54° (ffl:
20.28 Synthesis Example 2 (C compound, (R)-1-azido-2-hydroxy-
Synthesis of 3-phenylpropane) (R) obtained in Synthesis Example 1 above in a 200 m capacity reactor
-1-chloro-2-hydroxy-3-phenylpropane (B) 5. 70 d of dimethylformamide solution containing OOg (29.30 mmol) was added, and 3.81 g (58.60 mmol) of sodium azide was added at 0°C.
The mixture was stirred and reacted for 14 hours. After repulsion, water was added and extracted with ether, and the ether layer was washed successively with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 6.24 g8 of a brown oil. Add this to silica gel 200
(R)-1-azido-2-hydroxy-3-phenylpropane (C) was subjected to column chromatography packed with
4.84Cl (yield 93%) was obtained.

The properties of the above compound C are as follows.

Boiling point 145°C (18 mn+Hg, Kugelrohr apparatus) [α co. +2.76° (Cm2.10.
CH(J3)I Rνmax Cm-' 3420
(OH), 2120 (83) NMR (CDα3
) δ: 2.02 (1N, d, J = 5.2Hz.

exchangeable with 020,0
H) 2.80 (2H, d, J= 6.6Hz,
aromatic-C! i2-> 3.28~3.37 <2H,m, -Cjj2-
N3) 3.86~4.08 (IH, m, -C!1
(OH) -) 7.26 (5H, m, aromati
c H) MS (m/e), 149 (M”-N
2), 91 (100%) Synthesis Example 3 (Synthesis of D-(A) Compound, (R)-1-and-2-1-butoxycarboxy-3-phenylpropane) (R )-1-azido-2-hydroxy-3-phenylpropane (C) 101 mg (
1 ml of dichloromethane solution containing >0.56 mmol
1 of di-t-butoxycarboxylic anhydride (3,38 mmol) and 1.411 n1 of triethylamine (10,15 mmol) were placed in a reactor with a capacity of 10 d.
1) was added thereto, and the mixture was stirred at room temperature under an argon atmosphere for 90 hours to react. After the reaction, dichloromethane was added and the organic layer was diluted with
% hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, and dried over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a brown oily residue. This was subjected to column chromatography packed with 5 g of silica gel, and ether:hexane=1:2
(R)-1-Azide-2 as a colorless oil from the 0 (volume) stream
-t-butoxycarboxy-3-phenylpropane (D
-(a)) 137 mO (yield 88%) was obtained.

The properties of the compound D-(a) are as follows.

Boiling point 125°C (1, Omm Hg, Kugelrohr apparatus) [α] o + 18.28° (Cm2.22.C
HO23)r RvmaX Cm-' 2120 (
N3) NMR (CDCb) δ: 1.46 (9H,S, 0CO2-C(CH
3) 3)2.89~3.03 (2H, dd, a
romatic -CH2-)3.32-3. /13
(2N, m, -CH2-N3)4.82~5
．． 10 (1N, m, -CM-OCO2t-Bu
)7.25 (5H, m, aromatic H)
MS (m/e), 160 (M+-OCO-t-B
u).

103 (100%) Elemental analysis Cl4H1903N3 theoretical value C: 60.63. I-
(: 6.91°N: 15.15 Measured value C: 61.00. H: 6.65°N: 15
．． 15 Synthesis Example 4 (Synthesis of D-(b) Compound, (R)-1-azido-2-acetoxy-3-phenylpropane) (R)-1-azido-2-hydroxy- obtained in Synthesis Example 2 3-phenylpropane (C) 1.23 (11 (6,94 m mo
1.23 d of pyridine solution containing 1.23 d of pyridine (15.
27m mol) was placed in a reactor with a capacity of 10ml, and anhydrous vinegar (10.72d (7.63m
mol> was added dropwise and reacted with stirring at the same temperature for 24 hours. After the reaction, the solvent was distilled off under reduced pressure, ether was added, and the organic layer was mixed with 5% hydrochloric acid and saturated aqueous sodium bicarbonate.

Wash sequentially with saturated saline! iii[After drying with magnesium acid, the solvent was distilled off under reduced pressure to obtain a residue of 1.49
A portion of 3 g (0.1815 CI) was subjected to distillation to obtain (R)-1--azido-2-7cetoxy-3-phenylpropane (D = (b) > 0.1710 Cl (yield 93%)) as a colorless oil. I got it.

The properties of the above D-(b) compound are as follows.

Boiling point 84°C (0.85mm Hg, Kugelrohr apparatus) [α]D+7.12° (Cm2.13.CH
(43)IRl)max cm-' 2120(N3
>, 1740 (Cm 0) NMR (CDCf13) δ: 2.10 (3N, S, OCOCH3)
2.88~2.99 (2N, m, aromat
IC-CL! -) 3.27~3.38 (2N, m
, -C, Dan2-N3) 5.05~5.30 (I
H, m, -Cti(OAc>->7.21 (5H
, m, aromatic H) MS (m/e),
219 (M), 91 (loo%) Elemental analysis C11H1302N3 Theoretical value C: 60.26. l
-(: 5.98°N: 19.15 Measured value C: 59.98. H: 5.82°N: 19.
28 Synthesis Example 5 (Synthesis of D-(iii) Compound, (R)-1-azido-2-benzoxy-3-phenylpropane) (R)-1-azido-2-hydroxy- obtained in Synthesis Example 2 3-phenylpropane (C) 291,7ma (1,646m
10 m of dichloromethane 3d solution containing mof
1 into the reactor, pyridine 0,297! (3,621
m mol ) and benzoyl chloride 0.217 (1,8
11 mmol> was added thereto, and the mixture was reacted with stirring for 46 hours at air temperature under an argon atmosphere. After the reaction, the solvent was distilled off under reduced pressure, ether was added, and the organic layer was washed successively with 5% hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give a pale yellow color. An oily residue was obtained.

This was subjected to column chromatography packed with silica gel ioog, and ether:hexane=1:30 (volume)
A colorless oil (R)-1-azido-2-benzoxy-3-phenylpropane (D-(huff) 0.40
52(] (yield 87.6%) was obtained.

The properties of the above D-(iii) compound are as follows.

IRvmaX Cm-' 2120 (N3), 1
720 (Cm 0) NMR (CDα3) δ: 3.04-3.16 (2N, m, aro(
lIatic -CH2-)3.40~3.52 (
2)1. m, -CH2-N3)5.29-5.
56 (t)1. m, -CH(0COPh)-
>7.27 (5H, m, aromatic tl
)7.43~7.60 (3N, m, aromat
ic H) 8.00-8.13 (2H, m, aro
matic H) Synthesis Example 6 (Synthesis of E-(a) compound, (R)-4-azido-3-t-butoxycarboxybutyric acid) (R)-1-azido-2 obtained in Synthesis Example 3 above
-t-butoxycarboxy-3-phenylpropane (D
-(A) > 123.5ma (0,445mm
of> contains CcJla :CH3CN: [20=
2: 2: 3 (volume @) solution 3.5rdl to volume 10
d into the reactor, RUCI13・3120 2.56
m(1(0,0098m mol> and Na1Oa
2.28 g (10°68 mmol) was added and reacted with stirring at air temperature under an argon atmosphere for 120 hours.

After the reaction, 10% hydrochloric acid was added, extracted with dichloromethane, and dried over magnesium sulfate.The solvent was distilled off under reduced pressure.Ether was added to the residue, which was filtered through Celite. The ether layer of the filtrate was extracted with saturated aqueous sodium bicarbonate solution, and then the aqueous layer was acidified with concentrated hydrochloric acid, extracted with ether, and dried over magnesium sulfate.

The brown oil obtained by distilling off the solvent under reduced pressure was subjected to column chromatography packed with 4.4 g of silica gel washed with methanol to obtain chloroform:methanol=3:1.
(Volume) From the flow, (R)-4-and-3-t-butoxycarlevoxybutyro 1 (E-(I)) 63.5 m (J
(yield 58%) and its deacylation resulted in (R)-
4-azido-3-hydroxyacetic acid (F) 14.9ma
(23% yield) were obtained (E-(a) and F total yield 81%).

The properties of the obtained (R)-4-azido-3-t-butoxycarboxylic acid 1 (E-(a)) are as follows. Further, the infrared absorption spectrum of the E-(a) compound is shown in FIG.

[α], +13.12° (C=0.442,
CHCb) I Rv max cm-13400~2
800 (OH).

2110 (N3), R30 (C=O) NMR
(CDC13) δ: 1.50 (9H,S, 0COC(CH3)
3)2.76 (2)1. d, J=6.4
Hz, -Ct12-COOH) 3.52 to 3.57 (
2H,m, -Ch-N3)5.07~5.26
(1M, m, -C!1(OCOOt -Btu)
)8.09 (IH, br, s, exchange
able with D20, -COO MS (m/e), 217 (M+-82), 8
3 (100%) Synthesis Example 7 (Synthesis of E-(B) Compound, (R)-4-azido-3-acetoxyacetic acid) Crude product (R)- before purification by distillation obtained in Synthesis Example 4 above 1-azido-2-7cetoxy-3-phenylpropane (D-(ro)) 1.3093(](5゜5
CH3CN: 82
0 = 2: 2: 3 (volume) 18 d of solution to 5 volumes
Put it in a 0d reactor and add RLIC13・3t120 to it.
32. Omg (0,122mm01) and Na10
434.5(1(0,8111101>) was added and reacted with stirring at room temperature under an argon atmosphere for 120 hours. The purification treatment after the reaction was carried out in the same manner as in Synthesis Example 6 to obtain the (R)-
4-azido-3-acetoxybutyric acid (E-(b)) 0
．． 9071 () was obtained. A portion of this (0.2115 g) was subjected to column chromatography packed with purified silica gel 10 () (washed with methanol), and purified ( R)-4-azido-
3-acetoxybutyric acid (E-(b)) 0.2007
! ] (Yield 83%) was obtained.

The properties of the purified E-(b) compound are as follows.The infrared absorption spectrum of this E-(b) is
Shown in the figure.

[α]. +4,69° (C=0.940.CM
α3) f Rv max cm-' 3500~28
00 (Off).

2120 (N3 > , 1740 (C=O)N
MR (CDC13) δ: 2.10 (311,s, 0COC!j3)
2.74 (2H, d, J= 6.7Hz, -C
H2C00H)3.47~3.55 (2H,m, -
C1j2-N3)5.20~5.45 (IH, m
, -CM (OCOCH3) )9.89 (lH
,br,s, exchangeable with
20,,-COOH) MS(m/e), 1'i'O(M+-1), 1
09 (100%) Synthesis Example 8 (Synthesis of E-(iii) compound, (R)-4-azido-3-benzoxyacetic acid) (R)-1-azido-2 obtained in Synthesis Example 5 above
-Benzoxy-3-phenylpropane (D-(c))
232.2m (CC4 including 1 (0,826m mof>) 4:CH3CN: 820 =12: 2:
3 (volume) 10.5 ml of the solution was put into a 130 d reactor, and 75 mg of RuCl23.3H204 was added to it.
', 0.0182 m mol) and NaIO44,5
9fj (21,48 m mof >) was added and reacted with stirring at room temperature under an argon atmosphere for 34 hours. After the reaction, the pale yellow oil (R)-4 was treated in the same manner as in Synthesis Example 6.
-Azido-3-benzoxybutyric acid (E-(c)) 176.
3 mq (yield 85.6%) was obtained. This product was so pure that it did not require purification by column chromatography.

The obtained (R)-4-azido-3-benzoxy acid M (
The properties of E-(c)) are as follows.

Moreover, the infrared spectrum of this compound E-(c) is shown in FIG.

■Rv max cm-13500~2800 (ON
).

2120 (N3), 1720 (C=0)N
MR (CDCJ2:+) δ:2.90 (2H, dd, J=6.7Hz,
-CH2-COOH)3.60~3.72 (2H,
m, -CH2-N3)5.50~5.65 (IH
,m, -CM (0COf)h) -)6.61 (
1m, br, s, exchangeable vi
thD20, C00N> 7.45-7.60 (3H, m, aromatic
H) 7.98-8.11 (2H, m, aroma
tic H>Synthesis Example 9 (Synthesis of Compound F, (R)-4-azido-3-hydroxybutyric acid) (R)-4-azido-3- obtained in Synthesis Example 6
t-Butoxycarboxybutyric acid (E-(a)) 798m(
] (33.26 mmol) was placed in the same reactor as in Synthesis Example 6, and CF3COOH2.57d was added dropwise at 0°C under an argon stream to react with 1.
The reaction was allowed to proceed with stirring for 7 hours. After the reaction, the solvent was distilled off under reduced pressure, leaving an oily (R)-4-azido-3-hydroxy acid! (F) 472 mg (yield 100%)
I got it.

The properties of the above (R)-4-azido-3-hydroxybutyric acid (F) are as follows. Moreover, the infrared absorption spectrum of this compound (F) is shown in FIG.

[α]. +19.93° (C= 2.408.C
HCl3)IRνmaxcm-13500~2800(
OH).

2120 (N3), 1740 (C=0)N
MR(CD(J3) δ:2.60(2H,d, J=6.4Hz, -
Cdan2-COOH)3.40 (2tl, m, -C
jj2-N3)4.10~4.38(IH,m,-
Cjj (0 old -) 6.90 (2H, br, s, ex
changeable with[)20, -DH-
and -COOH-)MS (m/e), 128
(M-0H), 42 (100%) Synthesis Example 1
0 (Synthesis of Compound F, 4-and-3-hydroxybutyric acid) Crude product (R)-4-azido-3-acetoxybutyric acid (E-(RO)) obtained in Synthesis Example 7 before purification by column chromatography 0.6010! ;I <3.
Water containing 05 mmol: methanol = 1:9 (volume)
10 ml of the solution was placed in a reactor similar to Synthesis Example 6, and NaOH0,244 (J (6.10 mol)) was added thereto and reacted with stirring for 1 hour at air temperature under an argon stream. After the reaction, methanol was distilled off. The mixture was acidified with concentrated hydrochloric acid and extracted with ether. The solvent was distilled off under reduced pressure to obtain 484.4 mg of a pale yellow oil. This was washed with methanol and subjected to column chromatography packed with silica gel 15 (J). , 427 mg of oily (R)-4-azido-3-hydroxy acid M(F) from the chloroform stream (yield 9
6.5%). The properties of this product were consistent with those of Compound F obtained in Synthesis Example 9.

Synthesis Example 11 (Synthesis of Compound F, (R)-4-azido-3-hydroxybutyric acid) (R)-4-azido-3-benzoxybutyric acid (E -(c) > 56. On+g (
0.22 mmol) was placed in a reaction vessel similar to Synthesis Example 6, and 2 CO348 was added to the reaction vessel.
, 5mp (0.35m mof) was added and reacted with stirring at air temperature under an argon atmosphere for 144 hours. After the reaction, the solvent was distilled off under reduced pressure, ether was added, and the aqueous layer was extracted with saturated aqueous sodium bicarbonate. The mixture was made acidic with concentrated hydrochloric acid, extracted again with ether, and dried over magnesium sulfate.The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography packed with silica gel I,OG washed with methanol. (f?)-4-azido-3-hydroxybutyric acid (F) 32.8m (1 (yield 8 including synthesis example 8)
6%). The properties of this product were consistent with those of Compound F obtained in Synthesis Example 9.

Examples Compound F obtained by Synthesis Examples 9 to 11, (R)-4
Compound G, (R)-4-amino-3-hydroxybutyric acid, which is the object of the present invention, was synthesized using -azido-3-hydroxybutyric acid.

The above F compound 101.8m(J (0,702mol
) methanol solution containing 2. Od wo yo 1io7! 10.2 mg of palladium-carbon powder (palladium content: 10% by weight) was added thereto, and the mixture was reacted with stirring at air temperature under a hydrogen stream for 14 hours. After the reaction, a solution of water:methanol=3:7 (volume) was added, and the mixture was filtered through Celite'a. The solvent of the filtrate was distilled off under reduced pressure, and the remaining bacterial crystals were recrystallized from aqueous ethanol to obtain the target product in the form of colorless needles, (R)-
4-amino-3hydroxybutyric acid (G) 77n+c+(
A yield of 92%) was obtained.

The properties of this product are as follows.

Melting point 212°C (known compound 212°C) [α]. −
23,17° (C=0.492.water), (known compound [α] D-21,06°) IRy max cm-13430, 3200-250
0 (OH).

2110, 1620.1580~150ONMR (CD
C13) δ: 2.33 (2H, J= 6.6H2, -C)j2
-COOH) 2.85 to 3.04 (2H, m, -Cji
2NH3) 3.85 to 4.30 (IH, m, -(J
j (OH) −') MS (m/e), 119 (M
), 29 (100%) C4H9N theoretical value C:
40.33. H near, 62°N: 11.76 Measured value C: 40.03. H: 7.80°N:
11.81 The above NMR was consistent with the NMR assignment of a known racemic preparation. Furthermore, the behavior on cellulose thin layer chromatography was consistent with known racemic preparations.

(Effects of the Invention) The method of the present invention provides a raw material compound with very high optical purity, (
Since R)-4-azido-3-hydroxybutyric acid is used, biologically active (R)-form 4-amino-3-hydroxybutyric acid can be obtained with high purity and high yield, and this raw material compound can be obtained with high purity and high yield. It is also economical because it can be obtained in good yield through a simple reaction process.

[Brief explanation of the drawing]

Figures 1 to 3 show the raw material compounds of the present invention, (R)-4-azido-3, obtained in Synthesis Examples 6 to 8, respectively.
FIG. 4 is an infrared absorption spectrum of an optically active (R)-butyric acid derivative which is a precursor of -hydroxybutyric acid. This is the infrared absorption spectrum of

Claims (2)

[Claims] (1) 4-azido-3-hydroxybutyric acid represented by the following formula is hydrogenated in the presence of a catalyst.
Method for producing amino-3-hydroxybutyric acid. ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (2) The production method according to claim 1, wherein 4-azido-3-hydroxybutyric acid is an optical isomer.